Russian Journal of AllergyRussian Journal of AllergyРоссийский Аллергологический Журнал1810-88302686-682XPublishing House ABV Press1695910.36691/RJA16959ReviewsНаучные обзорыResearch ArticleRole of glucocorticoid receptor beta in the development of steroid resistanceРоль глюкокортикоидного рецептора бета в развитии резистентности к глюкокортикоидамhttps://orcid.org/0009-0001-7678-2489ParshinaVeronika A.ПаршинаВероника Анатольевна
Russian Federation
parshina.nicka@yandex.ruhttps://orcid.org/0000-0002-1620-84777849-7475KadushkinAliaksei G.КадушкинАлексей Геннадьевич
Belarus

MD, Dr. Sci. (Medicine), Assistant Professor

доктор медицинских наук, доцент

kadushkyn@gmail.comhttps://orcid.org/0000-0002-0668-28882449-5730TaganovichAnatoli D.ТагановичАнатолий Дмитриевич
Belarus

MD, Dr. Sci. (Medicine), Professor

доктор медицинских наук, профессор

taganovich@bsmu.byhttps://orcid.org/0000-0001-5343-42306008-7323ShilovskiyIgor P.ШиловскийИгорь Петрович
Russian Federation

Dr. Sci. (Biology)

доктор биологических наук

ip.shilovsky@nrcii.ruhttps://orcid.org/0000-0001-6444-64997555-5925ShershakovaNadezda N.ШершаковаНадежда Николаевна
Russian Federation

Dr. Sci. (Biology)

доктор биологических наук

nn.shershakova@nrcii.ruhttps://orcid.org/0000-0003-4961-96403199-9803KhaitovMusa R.ХаитовМуса Рахимович
Russian Federation

MD, Dr. Sci. (Medicine), corresponding member of the Russian Academy of Sciences

доктор медицинских наук, профессор, чл.-корр. РАН

mr.khaitov@nrcii.ruNational Research Center — Institute of Immunology Federal Medical-Biological Agency of RussiaГосударственный научный центр «Институт иммунологии»Belarusian State Medical UniversityБелорусский государственный медицинский университетThe Russian National Research Medical University named after N.I. PirogovРоссийский национальный исследовательский медицинский университет имени Н.И. Пирогова07102024241020242133823942507202423082024Copyright ©; 2024, Pharmarus Print MediaCopyright ©; 2024, Фармарус Принт Медиа2024Pharmarus Print MediaФармарус Принт Медиаhttps://rusalljournal.ru/raj/article/view/16959

Glucocorticoids are the most commonly used anti-inflammatory drugs for the treatment of inflammatory diseases, despite the fact that the resistance to them is increasing due to various circumstances. glucocorticoids insensitivity is an important clinical issue that is associated with life-threatening disease progression. Currently, there is no reliable biomarker that can be used to define steroid resistance. According to several studies, increased expression of the glucocorticoid receptor beta (GR-β) isoform is associated with steroid resistance.

In this review authors analyse the correlation between GR-β expression and the occurrence of steroid therapy-resistant diseases and to determine its potential as a biomarker. This review summarizes studies that point out increased GR-β expression in steroid-resistant groups of patients compared to steroid-sensitive groups. Articles included in the review focus on asthma, nasal polyposis, ulcerative colitis, and other chronic inflammatory diseases in which resistance to steroid therapy is observed. GR-β levels have also been shown to be elevated in patients with allergic rhinitis, Crohn’s disease and rheumatoid arthritis. In most studies, higher levels of GR-β were detected in peripheral blood mononuclear cells by reverse transcription polymerase chain reaction. Increased expression of GR-β is mostly associated with steroid resistance.

Thus, it can potentially be used as a biomarker of steroid resistance-related disorders.

Глюкокортикоиды являются наиболее используемыми противовоспалительными препаратами для лечения различных заболеваний, несмотря на то что резистентность к ним растёт ввиду различных обстоятельств. Нечувствительность к глюкокортикоидам является сложной клинической проблемой, которая связана с опасным для жизни прогрессированием заболевания. В настоящее время не существует биомаркера, который можно было бы использовать для определения резистентности к этим препаратам. Согласно ряду исследований, резистентность к глюкокортикоидам опосредована повышенной экспрессией изоформы глюкокортикоидного рецептора бета (GR-β).

В обзоре проведён анализ данных литературы о корреляции между экспрессией глюкокортикоидного рецептора бета (GR-β) и развитием заболеваний, резистентных к терапии глюкокортикоидами, а также определение его потенциала в качестве биомаркера. В обзор включены исследования, в которых выявлена повышенная экспрессия глюкокортикоидного рецептора бета (GR-β) у пациентов, резистентных к терапии глюкокортикоидами, в сравнении с чувствительными к ним пациентами. Статьи, включённые в обзор, посвящены бронхиальной астме, полипозному риносинуситу, язвенному колиту и другим хроническим воспалительным заболеваниям, при которых отмечалась резистентность к терапии глюкокортикоидами. При анализе данных установлено, что уровень глюкокортикоидного рецептора бета (GR-β) повышен у пациентов с аллергическим ринитом, болезнью Крона и ревматоидным артритом. В большинстве исследований более высокие уровни глюкокортикоидного рецептора бета (GR-β) выявлены в мононуклеарных клетках периферической крови методом полимеразной цепной реакции с обратной транскрипцией. Повышенная экспрессия глюкокортикоидного рецептора бета (GR-β) в большинстве случаев связана с развитием у пациентов резистентности к терапии глюкокортикоидами.

Таким образом, глюкокортикоидный рецептор бета (GR-β) потенциально может быть использован в качестве биомаркера нарушений, связанных с развитием стероидной резистентности.

glucocorticoidsglucocorticoid receptor betasteroid-resistant diseasebronchial asthmanasal polyposisulcerative colitisглюкокортикоидыглюкокортикоидный рецептор бетазаболевание, резистентное к терапии глюкокортикоидамибронхиальная астмаполипозный риносинуситязвенный колитThe work was supported by Russian Science Foundation grant № 23-45-10031 (https://rscf.ru/project/23-45-10031)Поисково-аналитическая работа выполнена при поддержке гранта Российского научного фонда № 23-45-10031 (https://rscf.ru/project/23-45-10031)Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory diseases. Lancet. 2009;373(9678):1905–1917. doi: 10.1016/S0140-6736(09)60326-3Barnes P.J., Adcock I.M. Glucocorticoid resistance in inflammatory diseases // Lancet. 2009. Vol. 373, N 9678. P. 1905–1917. doi: 10.1016/S0140-6736(09)60326-3Yang N, Ray DW, Matthews LC. Current concepts in glucocorticoid resistance. Steroids. 2012;77(11):1041–1049. doi: 10.1016/j.steroids.2012.05.007Yang N., Ray D.W., Matthews L.C. Current concepts in glucocorticoid resistance // Steroids. 2012. Vol. 77, N 11. P. 1041–1049. doi: 10.1016/j.steroids.2012.05.007Wilkinson L, Verhoog NJ, Louw A. Disease- and treatment-associated acquired glucocorticoid resistance. Endocr Connect. 2018;7(12):R328–R349. doi: 10.1530/EC-18-0421Wilkinson L., Verhoog N.J., Louw A. Disease- and treatment-associated acquired glucocorticoid resistance // Endocr Connect. 2018. Vol. 7, N 12. P. R328–R349. doi: 10.1530/EC-18-0421Chikanza IC, Kozaci DL. Corticosteroid resistance in rheumatoid arthritis: Molecular and cellular perspectives. Rheumatology. 2004;43(11):1337–1345. doi: 10.1093/rheumatology/keh333Chikanza I.C., Kozaci D.L. Corticosteroid resistance in rheumatoid arthritis: Molecular and cellular perspectives // Rheumatology (Oxford). 2004. Vol. 43, N 11. P.1337–1345. doi: 10.1093/rheumatology/keh333Rodriguez JM, Monsalves-Alvarez M, Henriquez S, et al. Glucocorticoid resistance in chronic diseases. Steroids. 2016;115:182–192. doi: 10.1016/j.steroids.2016.09.010Rodriguez J.M., Monsalves-Alvarez M., Henriquez S., et al. Glucocorticoid resistance in chronic diseases // Steroids. 2016. Vol. 115. P. 182–192. doi: 10.1016/j.steroids.2016.09.010Barnes PJ. Mechanisms and resistance in glucocorticoid control of inflammation. J Steroid Biochem Mol Biol. 2010;120(2-3):76–85. doi: 10.1016/j.jsbmb.2010.02.018Barnes P.J. Mechanisms and resistance in glucocorticoid control of inflammation // J Steroid Biochem Mol Biol. 2010. Vol. 120, N 2-3. P. 76–85. doi: 10.1016/j.jsbmb.2010.02.018Schäcke H, Döcke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002;96(1):23–43. doi: 10.1016/s0163-7258(02)00297-8Schäcke H., Döcke W.D., Asadullah K. Mechanisms involved in the side effects of glucocorticoids // Pharmacol Ther. 2002. Vol. 96, N 1. P. 23–43. doi: 10.1016/s0163-7258(02)00297-8Reichardt HM, Schütz G. Glucocorticoid signalling--multiple variations of a common theme. Mol Cell Endocrinol. 1998;146(1-2):1–6. doi: 10.1016/s0303-7207(98)00208-1Reichardt H.M., Schütz G. Glucocorticoid signalling--multiple variations of a common theme // Mol Cell Endocrinol. 1998. Vol. 146, N 1-2. P. 1–6. doi: 10.1016/s0303-7207(98)00208-1Frank F, Ortlund EA, Liu X. Structural insights into glucocorticoid receptor function. Biochem Soc Trans. 2021;49(5):2333–2343. doi: 10.1042/BST20210419Frank F., Ortlund E.A., Liu X. Structural insights into glucocorticoid receptor function // Biochem Soc Trans. 2021. Vol. 49, N 5. P. 2333–2343. doi: 10.1042/BST20210419Pujols L, Mullol J, Torrego A, Picado C. Glucocorticoid receptors in human airways. Allergy. 2004;59(10):1042–1052. doi: 10.1111/j.1398-9995.2004.00635.xPujols L., Mullol J., Torrego A., Picado C. Glucocorticoid receptors in human airways // Allergy. 2004. Vol. 59, N 10. P. 1042–1052. doi: 10.1111/j.1398-9995.2004.00635.xOakley RH, Webster JC, Sar M, et al. Expression and subcellular distribution of the beta-isoform of the human glucocorticoid receptor. Endocrinology. 1997;138(11):5028–5038. doi: 10.1210/endo.138.11.5501Oakley R.H., Webster J.C., Sar M., et al. Expression and subcellular distribution of the beta-isoform of the human glucocorticoid receptor // Endocrinology. 1997. Vol. 138, N 11. P. 5028–5038. doi: 10.1210/endo.138.11.5501Lewis-Tuffin LJ, Cidlowski JA. The physiology of human glucocorticoid receptor beta (hGRbeta) and glucocorticoid resistance. Ann NY Acad Sci. 2006;1069:1–9. doi: 10.1196/annals.1351.001Lewis-Tuffin L.J., Cidlowski J.A. The physiology of human glucocorticoid receptor beta (hGRbeta) and glucocorticoid resistance // Ann NY Acad Sci. 2006. Vol. 1069. P. 1–9. doi: 10.1196/annals.1351.001Kubin ME, Hägg PM, Kokkonen N, et al. Glucocorticoid receptors GRα and GRβ are expressed in inflammatory dermatoses. Eur J Dermatol. 2016;26(1):21–27. doi: 10.1684/ejd.2015.2691Kubin M.E., Hägg P.M., Kokkonen N., et al. Glucocorticoid receptors GRα and GRβ are expressed in inflammatory dermatoses // Eur J Dermatol. 2016. Vol. 26, N 1. P. 21–27. doi: 10.1684/ejd.2015.2691Chuchalin AG, Avdeev SN, Aisanov ZR, et al. Аsthma. Russ J Allergy. 2021;18(4):40–106. EDN: PQIFPT doi: 10.36691/RJA1500Чучалин А.Г., Авдеев С.Н., Айсанов З.Р., и др. Бронхиальная астма // Российский аллергологический журнал. 2021. Т. 18, № 4. С. 40–106. EDN: PQIFPT doi: 10.36691/RJA1500Goleva E, Hauk PJ, Boguniewicz J, et al. Airway remodeling and lack of bronchodilator response in steroid-resistant asthma. J Allergy Clin Immunol. 2007;120(5):1065–1072. doi: 10.1016/j.jaci.2007.07.042Goleva E., Hauk P.J., Boguniewicz J., et al. Airway remodeling and lack of bronchodilator response in steroid-resistant asthma // J Allergy Clin Immunol. 2007. Vol. 120, N 5. P. 1065–1072. doi: 10.1016/j.jaci.2007.07.042Poroshina AS, Shershakova NN, Shilovskiy IP, et al. Role of IL-25, IL-33 and TSLP in the development of corticosteroid resistance. Immunologiya. 2023;44(4):500–510. EDN: CJBRCC doi: 10.33029/0206-4952-2023-44-4-500-510Порошина А.С., Шершакова Н.Н., Шиловский И.П., и др. Роль ИЛ-25, ИЛ-33 и TSLP в развитии кортикостероидной резистентности // Иммунология. 2023. Т. 44, № 4. С. 500–510. EDN: CJBRCC doi: 10.33029/0206-4952-2023-44-4-500-510Sousa AR, Lane SJ, Cidlowski JA, et al. Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor beta-isoform. J Allergy Clin Immunol. 2000;105(5):943–950. doi: 10.1067/mai.2000.106486Sousa A.R., Lane S.J., Cidlowski J.A., et al. Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor beta-isoform // J Allergy Clin Immunol. 2000. Vol. 105, N 5. P. 943–950. doi: 10.1067/mai.2000.106486Hamid QA, Wenzel SE, Hauk PJ, et al. Increased glucocorticoid receptor β in airway cells of glucocorticoid-insensitive asthma. Am J Respir Crit Care Med. 1999;159(5, Pt 1):1600–1604. doi: 10.1164/ajrccm.159.5.9804131Hamid Q.A., Wenzel S.E., Hauk P.J., et al. Increased glucocorticoid receptor β in airway cells of glucocorticoid--insensitive asthma // Am J Respir Crit Care Med. 1999. Vol. 159, N 5, Pt. 1. P. 1600–1604. doi: 10.1164/ajrccm.159.5.9804131Leung DY, Hamid Q, Vottero A, et al. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor β. J Exp Med. 1997;186(9):1567–1574. doi: 10.1084/jem.186.9.1567Leung D.Y., Hamid Q., Vottero A., et al. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor β // J Exp Med. 1997. Vol. 186, N 9. P. 1567–1574. doi: 10.1084/jem.186.9.1567Goleva E, Jackson LP, Gleason M, Leung DY. Usefulness of PBMCs to predict clinical response to corticosteroids in asthmatic patients. J Allergy Clin Immunol. 2012;129(3):687–693. doi: 10.1016/j.jaci.2011.12.001Goleva E., Jackson L.P., Gleason M., Leung D.Y. Usefulness of PBMCs to predict clinical response to corticosteroids in asthmatic patients // J Allergy Clin Immunol. 2012. Vol. 129, N 3. P. 687–693. doi: 10.1016/j.jaci.2011.12.001Goleva E, Li L, Eves PT, et al. Increased glucocorticoid receptor β alters steroid response in glucocorticoid-insensitive asthma. Am J Respir Crit Care Med. 2006;173(6):607–616. doi: 10.1164/rccm.200507-1046ocGoleva E., Li L., Eves P.T., et al. Increased glucocorticoid receptor β alters steroid response in glucocorticoid-insensitive asthma // Am J Respir Crit Care Med. 2006. Vol. 173, N 6. P. 607–616. doi: 10.1164/rccm.200507-1046ocLi LB, Leung DY, Martin RJ, Goleva E. Inhibition of histone deacetylase 2 expression by elevated glucocorticoid receptor beta in steroid-resistant asthma. Am J Respir Crit Care Med. 2010;182(7):877–883. doi: 10.1164/rccm.201001-0015OCLi L.B., Leung D.Y., Martin R.J., Goleva E. Inhibition of histone deacetylase 2 expression by elevated glucocorticoid receptor beta in steroid-resistant asthma // Am J Respir Crit Care Med. 2010. Vol. 182, N 7. P. 877–883. doi: 10.1164/rccm.201001-0015OCSavlevich EL, Zurochka AV, Kurbacheva OM, et al. Pleiomorphism of the cytokine profile in nasal polyp tissue depending on the phenotype of chronic rhinosinusitis with nasal polyps. Vestnik otorinolaringologii. 2022;88(1):50–56. EDN: YRQNQC doi: 10.17116/otorino20228801150Савлевич Е.Л., Зурочка А.В., Курбачева О.М., и др. Плейоморфизм цитокинового профиля в ткани полипов в зависимости от фенотипа полипозного риносинусита // Вестник оториноларингологии. 2022. Т. 88, № 1. С. 50–56. EDN: YRQNQC doi: 10.17116/otorino20228801150Hamilos DL, Leung DY, Muro S, et al. GRbeta expression in nasal polyp inflammatory cells and its relationship to the anti-inflammatory effects of intranasal fluticasone. J Allergy Clin Immunol. 2001;108(1):59–68. doi: 10.1067/mai.2001.116428Hamilos D.L., Leung D.Y., Muro S., et al. GRbeta expression in nasal polyp inflammatory cells and its relationship to the anti-inflammatory effects of intranasal fluticasone // J Allergy Clin Immuno. 2001. Vol. 108, N 1. P. 59–68. doi: 10.1067/mai.2001.116428Xue JM, An YF, Suo LM, et al. Livin in synergy with Ras induces and sustains corticosteroid resistance in the airway mucosa. Int J Biol Sci. 2021;17(8):2089–2098. doi: 10.7150/ijbs.58427Xue J.M., An Y.F., Suo L.M., et al. Livin in synergy with Ras induces and sustains corticosteroid resistance in the airway mucosa // Int J Biol Sci. 2021. Vol. 17, N 8. P. 2089–2098. doi: 10.7150/ijbs.58427Li P, Li Y, Li YQ, et al. Glucocorticoid receptor expression and glucocorticoid therapeutic effect in nasal polyps. Clin Invest Med. 2010;33(3):181–188. doi: 10.25011/cim.v33i3.13724Li P., Li Y., Li Y.Q., et al. Glucocorticoid receptor expression and glucocorticoid therapeutic effect in nasal polyps // Clin Invest Med. 2010. Vol. 33, N 3. P. 181–188. doi: 10.25011/cim.v33i3.13724Choi BR, Kwon JH, Gong SJ, et al. Expression of glucocorticoid receptor mRNAs in glucocorticoid-resistant nasal polyps. Exp Mol Med. 2006;38(5):466–473. doi: 10.1038/emm.2006.55Choi B.R., Kwon J.H., Gong S.J., et al. Expression of glucocorticoid receptor mRNAs in glucocorticoid-resistant nasal polyps // Exp Mol Med. 2006. Vol. 38, N 5. P. 466–473. doi: 10.1038/emm.2006.55Ungaro R, Mehandru S, Allen PB, et al. Ulcerative colitis. Lancet. 2017;389(10080):1756–1770. doi: 10.1016/S0140-6736(16)32126-2Ungaro R., Mehandru S., Allen P.B., et al. Ulcerative colitis // Lancet. 2017. Vol. 389, N 10080. P. 1756–1770. doi: 10.1016/S0140-6736(16)32126-2Dubois-Camacho K, Ottum PA, Franco-Muñoz D, et al. Glucocorticosteroid therapy in inflammatory bowel diseases: From clinical practice to molecular biology. World J Gastroenterol. 2017;23(36):6628–6638. doi: 10.3748/wjg.v23.i36.6628Dubois-Camacho K., Ottum P.A., Franco-Muñoz D., et al. Glucocorticosteroid therapy in inflammatory bowel diseases: From clinical practice to molecular biology // World J Gastroenterol. 2017. Vol. 23, N 36. P. 6628–6638. doi: 10.3748/wjg.v23.i36.6628Liu C, Mo LH, Feng BS, et al. Twist1 contributes to developing and sustaining corticosteroid resistance in ulcerative colitis. Theranostics. 2021;11(16):7797–7812. doi: 10.7150/thno.62256Liu C., Mo L.H., Feng B.S., et al. Twist1 contributes to developing and sustaining corticosteroid resistance in ulcerative colitis // Theranostics. 2021. Vol. 11, N 16. P. 7797–7812. doi: 10.7150/thno.62256Fujishima S, Takeda H, Kawata S, Yamakawa M. The relationship between the expression of the glucocorticoid receptor in biopsied colonic mucosa and the glucocorticoid responsiveness of ulcerative colitis patients. Clin Immunol. 2009;133(2):208–217. doi: 10.1016/j.clim.2009.07.006Fujishima S., Takeda H., Kawata S., Yamakawa M. The relationship between the expression of the glucocorticoid receptor in biopsied colonic mucosa and the glucocorticoid responsiveness of ulcerative colitis patients // Clin Immunol. 2009. Vol. 133, N 2. P. 208–217. doi: 10.1016/j.clim.2009.07.006Orii F, Ashida T, Nomura M, et al. Quantitative analysis for human glucocorticoid receptor α/β mRNA in IBD. Biochem Biophys Res Commun. 2002;296(5):1286–1294. doi: 10.1016/S0006-291X(02)02030-2Orii F., Ashida T., Nomura M., et al. Quantitative analysis for human glucocorticoid receptor α/β mRNA in IBD // Biochem Biophys Res Commun. 2002. Vol. 296, N 5. P. 1286–1294. doi: 10.1016/S0006-291X(02)02030-2Semple JW, Rebetz J, Maouia A, Kapur R. An update on the pathophysiology of immune thrombocytopenia. Curr Opin Hematol. 2020;27(6):423–429. doi: 10.1097/MOH.0000000000000612Semple J.W., Rebetz J., Maouia A., Kapur R. An update on the pathophysiology of immune thrombocytopenia // Curr Opin Hematol. 2020. Vol. 27, N 6. P. 423–429. doi: 10.1097/MOH.0000000000000612Liang Y, Song MM, Liu SY, Ma LL. Relationship between expression of glucocorticoid receptor isoforms and glucocorticoid resistance in immune thrombocytopenia. Hematology. 2016;21(7):440–446. doi: 10.1080/10245332.2015.1102371Liang Y., Song M.M., Liu S.Y., Ma L.L. Relationship between expression of glucocorticoid receptor isoforms and glucocorticoid resistance in immune thrombocytopenia // Hematology. 2016. Vol. 21, N 7. P. 440–446. doi: 10.1080/10245332.2015.1102371Ma L, Fang M, Liang Y, et al. Low expression of glucocorticoid receptor alpha isoform in adult immune thrombocytopenia correlates with glucocorticoid resistance. Ann Hematol. 2013;92(7):953–960. doi: 10.1007/s00277-013-1705-5Ma L., Fang M., Liang Y., et al. Low expression of glucocorticoid receptor alpha isoform in adult immune thrombocytopenia correlates with glucocorticoid resistance // Ann Hematol. 2013. Vol. 92, N 7. P. 953–960. doi: 10.1007/s00277-013-1705-5Petagna L, Antonelli A, Ganini C, et al. Pathophysiology of Crohn’s disease inflammation and recurrence. Biology direct. 2020;15(1):23. doi: 10.1186/s13062-020-00280-5Petagna L., Antonelli A., Ganini C., et al. Pathophysiology of Crohn’s disease inflammation and recurrence // Biology direct. 2020. Vol. 15, N 1. P. 23. doi: 10.1186/s13062-020-00280-5Towers R, Naftali T, Gabay G, et al. High levels of glucocorticoid receptors in patients with active Crohn’s disease may predict steroid resistance. Clin Exp Immunol. 2005;141(2):357–362. doi: 10.1111/j.1365-2249.2005.02846.xTowers R., Naftali T., Gabay G., et al. High levels of glucocorticoid receptors in patients with active Crohn’s disease may predict steroid resistance // Clin Exp Immunol. 2005. Vol. 141, N 2. P. 357–362. doi: 10.1111/j.1365-2249.2005.02846.xSmolen JS, Aletaha D, Barton A, et al. Rheumatoid arthritis. Nat Rev Dis Primers. 2018;4:18001. doi: 10.1038/nrdp.2018.1Smolen J.S., Aletaha D., Barton A., et al. Rheumatoid arthritis // Nat Rev Dis Primers. 2018. Vol. 4. P. 18001. doi: 10.1038/nrdp.2018.1Kozaci DL, Chernajovsky Y, Chikanza IC. The differential expression of corticosteroid receptor isoforms in corticosteroid-resistant and -sensitive patients with rheumatoid arthritis. Rheumatology. 2007;46(4):579–585. doi: 10.1093/rheumatology/kel276Kozaci D.L., Chernajovsky Y., Chikanza I.C. The differential expression of corticosteroid receptor isoforms in corticosteroid-resistant and -sensitive patients with rheumatoid arthritis // Rheumatology. 2007. Vol. 46, N 4. P. 579–585. doi: 10.1093/rheumatology/kel276Matysiak M, Makosa B, Walczak A, Selmaj K. Patients with multiple sclerosis resisted to glucocorticoid therapy: Abnormal expression of heat-shock protein 90 in glucocorticoid receptor complex. Mult Scler J. 2008;14(7):919–926. doi: 10.1177/1352458508090666Matysiak M., Makosa B., Walczak A., Selmaj K. Patients with multiple sclerosis resisted to glucocorticoid therapy: Abnormal expression of heat-shock protein 90 in glucocorticoid receptor complex // Mult Scler J. 2008. Vol. 14, N 7. P. 919–926. doi: 10.1177/1352458508090666Guan YC, Jiang L, Ma LL, et al. Expression of glucocorticoid receptor isoforms and associations with serine/arginine-rich protein 30c and 40 in patients with systemic lupus erythematosus. Clin Exp Rheumatol. 2015;33(2):225–233.Guan Y.C., Jiang L., Ma L.L., et al. Expression of glucocorticoid receptor isoforms and associations with serine/arginine-rich protein 30c and 40 in patients with systemic lupus erythematosus // Clin Exp Rheumatol. 2015. Vol. 33, N 2. P. 225–233.Stokes K, Yoon P, Makiya M, et al. Mechanisms of glucocorticoid resistance in hypereosinophilic syndromes. Clin Exp Allergy. 2019;49(12):1598–1604. doi: 10.1111/cea.13509Stokes K., Yoon P., Makiya M., et al. Mechanisms of glucocorticoid resistance in hypereosinophilic syndromes // Clin Exp Allergy. 2019. Vol. 49, N 12. P. 1598–1604. doi: 10.1111/cea.13509Urzua CA, Guerrero J, Gatica H, et al. Evaluation of the glucocorticoid receptor as a biomarker of treatment response in Vogt-Koyanagi-Harada disease. Invest Ophthalmol Visual Sci. 2017;58(2):974–980. doi: 10.1167/iovs.16-20783Urzua C.A., Guerrero J., Gatica H., et al. Evaluation of the glucocorticoid receptor as a biomarker of treatment response in Vogt-Koyanagi-Harada disease // Invest Ophthalmol Visual Sci. 2017. Vol. 58, N 2. P. 974–980. doi: 10.1167/iovs.16-20783Shahidi H, Vottero A, Stratakis CA, et al. Imbalanced expression of the glucocorticoid receptor isoforms in cultured lymphocytes from a patient with systemic glucocorticoid resistance and chronic lymphocytic leukemia. Biochem Biophys Res Commun. 1999;254(3):559–565. doi: 10.1006/bbrc.1998.9980Shahidi H., Vottero A., Stratakis C.A., et al. Imbalanced expression of the glucocorticoid receptor isoforms in cultured lymphocytes from a patient with systemic glucocorticoid resistance and chronic lymphocytic leukemia // Biochem Biophys Res Commun. 1999. Vol. 254, N 3. P. 559–565. doi: 10.1006/bbrc.1998.9980Zhang X, Chen J, Gao Z, et al. Response of glucocorticoid receptor alpha and histone deacetylase 2 to glucocorticoid treatment predicts the prognosis of sudden sensorineural hearing loss. Clin Exp Otorhinolaryngol. 2019;12(4):367–375. doi: 10.21053/ceo.2018.01298Zhang X., Chen J., Gao Z., et al. Response of glucocorticoid receptor alpha and histone deacetylase 2 to glucocorticoid treatment predicts the prognosis of sudden sensorineural hearing loss // Clin Exp Otorhinolaryngol. 2019. Vol. 12, N 4. P. 367–375. doi: 10.21053/ceo.2018.01298Shilovskiy IP, Timotievich ED, Kaganova MM, et al. The role of the triad of respiratory epithelial cell-derived cytokines in the pathogenesis of allergic rhinitis. Immunologiya. 2024;45(2):245–55. EDN: VOHQMG doi: 10.33029/1816-2134-2024-45-2-245-255Шиловский И.П., Тимотиевич Е.Д., Каганова М.М., и др. Роль триады цитокинов, продуцируемых респираторным эпителием, в патогенезе аллергического ринита // Иммунология. 2024. Т. 45, № 2. С. 245–255. EDN: VOHQMG doi: 10.33029/1816-2134-2024-45-2-245-255Ishida A, Ohta N, Koike S, et al. Overexpression of glucocorticoid receptor-β in severe allergic rhinitis. Auris Nasus Larynx. 2010;37(5):584–588. doi: 10.1016/j.anl.2009.12.002Ishida A., Ohta N., Koike S., et al. Overexpression of glucocorticoid receptor-β in severe allergic rhinitis // Auris Nasus Larynx. 2010. Vol. 37, N 5. P. 584–588. doi: 10.1016/j.anl.2009.12.002Kino T, Manoli I, Kelkar S, et al. Glucocorticoid receptor (GR) beta has intrinsic, GRalpha-independent transcriptional activity. Biochem Biophys Res Commun. 2009;381(4):671–675. doi: 10.1016/j.bbrc.2009.02.110Kino T., Manoli I., Kelkar S., et al. Glucocorticoid receptor (GR) beta has intrinsic, GRalpha-independent transcriptional activity // Biochem Biophys Res Commun. 2009. Vol. 381, N 4. P. 671–675. doi: 10.1016/j.bbrc.2009.02.110Yudt MR, Jewell CM, Bienstock RJ, Cidlowski JA. Molecular origins for the dominant negative function of human glucocorticoid receptor beta. Mol Cell Biol. 2003;23(12):4319–4330. doi: 10.1128/MCB.23.12.4319-4330.2003Yudt M.R., Jewell C.M., Bienstock R.J., Cidlowski J.A. Molecular origins for the dominant negative function of human glucocorticoid receptor beta // Mol Cell Biol. 2003. Vol. 23, N 12. P. 4319–4330. doi: 10.1128/MCB.23.12.4319-4330.2003Wadhwa R, Dua K, Adcock IM, et al. Cellular mechanisms underlying steroid-resistant asthma. Eur Respir Rev. 2019;28(153):190096. doi: 10.1183/16000617.0096-2019Wadhwa R., Dua K., Adcock I.M., et al. Cellular mechanisms underlying steroid-resistant asthma // Eur Respir Rev. 2019. Vol. 28, N 153. P. 190096. doi: 10.1183/16000617.0096-2019Hearing SD, Norman M, Probert CS, et al. Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytes. Gut. 1999;45(3):382–388. doi: 10.1136/gut.45.3.382Hearing S.D., Norman M., Probert C.S., et al. Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytes // Gut. 1999. Vol. 45, N 3. P. 382–388. doi: 10.1136/gut.45.3.382Munkholm P, Langholz E, Davidsen M, Binder V. Frequency of glucocorticoid resistance and dependency in Crohn’s disease. Gut. 1994;35(3):360–362. doi: 10.1136/gut.35.3.360Munkholm P., Langholz E., Davidsen M., Binder V. Frequency of glucocorticoid resistance and dependency in Crohn’s disease // Gut. 1994. Vol. 35, N 3. P. 360–362. doi: 10.1136/gut.35.3.360Yudt MR, Cidlowski JA. The glucocorticoid receptor: Coding a diversity of proteins and responses through a single gene. Mol Endocrinol. 2002;16(8):1719–1726. doi: 10.1210/me.2002-0106Yudt M.R., Cidlowski J.A. The glucocorticoid receptor: Coding a diversity of proteins and responses through a single gene // Mol Endocrinol. 2002. Vol. 16, N 8. P. 1719–1726. doi: 10.1210/me.2002-0106Oakley RH, Jewell CM, Yudt MR, et al. The dominant negative activity of the human glucocorticoid receptor β isoform. J Biol Chem. 1999;274(39):27857–27866. doi: 10.1074/jbc.274.39.27857Oakley R.H., Jewell C.M., Yudt M.R., et al. The dominant negative activity of the human glucocorticoid receptor β isoform // J Biol Chem. 1999. Vol. 274, N 39. P. 27857–27866. doi: 10.1074/jbc.274.39.27857Oakley RH, Sar M, Cidlowski JA. The human glucocorticoid receptor β isoform. J Biol Chem. 1996;271(16):9550–9559. doi: 10.1074/jbc.271.16.9550Oakley R.H., Sar M., Cidlowski J.A. The human glucocorticoid receptor β isoform // J Biol Chem. 1996. Vol. 271, N 16. P. 9550–9559. doi: 10.1074/jbc.271.16.9550Hauk PJ, Goleva E, Strickland I, et al. Increased glucocorticoid receptor β expression converts mouse hybridoma cells to a corticosteroid-insensitive phenotype. Am J Respir Cell Mol Biol. 2002;27(3):361–367. doi: 10.1165/rcmb.4861Hauk P.J., Goleva E., Strickland I., et al. Increased glucocorticoid receptor β expression converts mouse hybridoma cells to a corticosteroid-insensitive phenotype // Am J Respir Cell Mol Biol. 2002. Vol. 27, N 3. P. 361–367. doi: 10.1165/rcmb.4861Webster JC, Oakley RH, Jewell CM, Cidlowski JA. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative β-isoform: A mechanism for the generation of glucocorticoid resistance. Proc Nat Acad Sci. 2001;98(12):6865–6870. doi: 10.1073/pnas.121455098Webster J.C., Oakley R.H., Jewell C.M., Cidlowski J.A. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative β-isoform: A mechanism for the generation of glucocorticoid resistance // Proc Nat Acad Sci. 2001. Vol. 98, N 12. P. 6865–6870. doi: 10.1073/pnas.121455098